Pharmaceutical and cosmetic formulations

ABSTRACT

Pharmaceutical and cosmetic formulations comprising hydrophobic highly disperse silicon dioxide with a tamped density of 70-400 g/l.

The invention relates to pharmaceutical and cosmetic formulations whichcomprise hydrophobic highly disperse silicon dioxide.

In a medicament a distinction is made between two substance groups withdifferent functions, namely active compounds and auxiliary substances.

The active compounds are characterized by their specific pharmacologicalaction. They are the active constituent of a medicament. As such, theyare also identified quantitatively on the packaging and on the packleaflet.

In addition to the actual active compound, medicaments compriseauxiliary substances or also adjuvants in order to convert the activecompound into suitable formulations which are active at the desired siteof use. A medicament conventionally comprises several auxiliarysubstances with different functions, for example fillers, binders,disintegrating agents, lubricants, greasing agents or mould releaseagents.

A large number of auxiliary substances can be resorted to in thedevelopment of stable, easy-to-handle and active medicaments from activecompound(s) and auxiliary substances.

Highly disperse silicon dioxide, such as, for example, Aerosil® 200, isan important auxiliary substance which is often employed forpharmaceutical and cosmetic formulations.

Highly disperse silicon dioxide is prepared by flame hydrolysis ofchlorosilanes and is therefore also called pyrogenic silicon dioxide. Itis listed in numerous pharmacopoeias as follows: “HochdispersesSiliciumdioxid” (German Pharmacopoeia); “Silica, Colloidal Anhydrous”(European Pharmacopoeia); “Colloidal Silicon Dioxide” (USPharmacopoeia/National Formulary), “Colloidal Anhydrous Silica” (BritishPharmacopoeia) and “Light Anhydrous Silicic Acid” (JapanesePharmacopoeia).

Highly disperse silicon dioxide can be used, for example, in solidproduct forms as a flow regulating agent, adsorbent and desiccant and inliquid and semi-solid product forms as a suspension stabilizer andmatrix- and gel-forming agent.

It can furthermore be used to increase the mechanical stability and therate of disintegration of tablets. It can moreover improve thedistribution of the active compound. In a few medicaments highlydisperse silicon dioxide also functions as the active compound.

Highly disperse, pyrogenic silicon dioxide has a high affinity for waterand is wetted completely by this. It is distinguished by hydrophilicproperties.

Hydrophobic highly disperse silicon dioxide, such as, for example,Aerosil® R 972, can have significant advantages over hydrophilic highlydisperse silicon dioxide in pharmaceutical and cosmetic compositions.Although it is not described in the Pharmacopoeia, it has therefore beenused by some pharmaceutical companies for many years. The Red List—thelist of medical preparations for Germany—thus names a number ofpreparations in which Aerosil® R 972 or methylated silicon dioxide ismentioned as an auxiliary substance.

Hydrophobic highly disperse silicon dioxide as a pharmaceutical rawmaterial is described generally by H. P. Fiedler, Lexikon derHilfsstoffe [Dictionary of Auxiliary Substances], Editio Cantor Verlag,Aulendorf. Aerosil® R 812 and R 972 are dealt with explicitly here.Information on the use of Aerosil® R 972 in pharmaceutical and cosmeticcompositions is moreover to be found in the publication series PigmenteNr. 49, Aerosil in Pharmazie und Kosmetik [Pigments no. 49, Aerosil inPharmacy and Cosmetics], Degussa.

Hydrophobic highly disperse silicon dioxide, such as, for example,Aerosil® R 972, is suitable as a flow regulator for hygroscopic,pulverulent substances. By the formation of a layer of Aerosil® R 972particles on the powder particles, the water (vapour) uptake thereof isreduced or slowed down (H. P. Fiedler, Lexikon der Hilfsstoffe[Dictionary of Auxiliary Substances], Editio Cantor Verlag Aulendorf,3rd edition, 1989). Furthermore, no film of water forms on the particlesof the hydrophobic silicon dioxide itself, so that the adhesive forcesbetween the “coated” powder particles remain low. In this manner, forexample, an addition of 0.5 wt. % Aerosil® R 972 acquires the flowproperties of maize starch even at high atmospheric humidities (H. v.Czetsch Lindenwald et al., J. Soc. Cosmetics Chemists 16 (1965) 251). Onthe other hand, if Aerosil® 200, which is hydrophilic, is used, lumpingtogether of hygroscopic substances—even with relatively high Aerosilcontents—often cannot be prevented. Hygroscopic powders contained incapsules also remain flowable by an addition of Aerosil® R 972, which ishydrophobic (H. P. Fiedler, Lexikon der Hilfsstoffe [Dictionary ofAuxiliary Substances], Editio Cantor Verlag Aulendorf, 3rd edition,1989).

Aerosil® R 972 can also be employed in the granulation of hygroscopicproducts, for example plant extracts. This is even possible from aqueoussolutions, so that organic solvents can be omitted. Hydrophilic silicondioxide is unsuitable here.

Aerosil® R 972 moreover improves the properties of powder raw materials.Thus, for example, the scatter value of kieselguhr is increasedeight-fold (F. Gstirner, Arch. Pharmz. 300 (1967) 757). Powders moreoverretain their consistency, even at high relative atmospheric humidities.

There are also advantages in tablet-making from hygroscopic powders orgranules. Hydrophobic highly disperse silicon dioxide is superior hereif a slow tablet disintegration or a delayed release of active compound,for example in the case of sustained release formulations, is to beachieved. Hydrophilic silicon dioxide accelerates tablet disintegrationin many cases, since it can be wetted by water and promotes thetransportation of water into the inside of the tablet in this manner(wick effect). Together with water-swellable compounds, it is thereforealso employed as a disintegrating agent. Since hydrophobic silicondioxide is not wetted by water, it shows no wick effect.

Some specific examples of sustained-release formulations for solid, oralmedicament forms with Aerosil® R 972 are described in the following:

In ibuprofen tablets Aerosil® R 972 reduces the release of activecompound to a greater degree than hydrophilic highly disperse silicondioxides (E. M. Samy et al.; Bull. Pharm. Sci. Assiut University 19(1996) 19).

If acetaminophen or theophylline is subjected to dry granulation withAerosil® R 972 and the resulting mixture is introduced into capsules,the active compound release rate thereof is reduced drastically. Anaddition of 0.6 wt. % Aerosil® R 972 is optimum. With this, 80-100% ofthe active compound is released within eight hours (V. R. Sista et al.;Drug Development and Industrial Pharmacy, 22 (1996) 153).

Aspartate tablets or mineral salt-containing gelatine capsules with aslow release of active compound can be prepared using Aerosil® R 972 (O.Gattnar, Slovakian Patent CS 236300, 1985, L. Gyarmati et al., HungarianPatent HU 26263, 1983). Capsules with a delayed release of activecompound are also described by Takeda Chem. Ind. Ltd., Japanese Patent 0823 9301, 1996. These contain a “network” of water-solublecarboxymethylcellulose and polyvalent salts, in which is enclosed theactive compound dissolved in water. According to the patentspecification, Aerosil® R 972 serves as an adsorbent.

Aerosil® R 972 is moreover the most effective flow auxiliary in hardgelatine capsule fillings (H. v. Czetsch-Lindenwald et al., J. Soc.Cosmetics Chemists 16 (1965) 251).

Hydrophilic highly disperse silicon dioxide is unsuitable forstabilizing or thickening w/o emulsions, since it migrates into theaqueous phase because of its hydrophilic character (H. v.Czetsch-Lindenwald, Pharm. Ind. 27 (1965) 300). In contrast,stabilization is effected with Aerosil® R 972, because this remains inthe oily phase as hydrophobic material and builds up a gel structurehere. W/o ointments formulated with Aerosil® R 972 thus still remainspreadable 10 to 20° C. above their melting point. The release ofaqueous active compounds from such bases is furthermore slowed down.

Aerosil® R 972 thickens balsam gels to a considerably lower degree thanhydrophilic highly disperse silicon dioxides. This is advantageous ifhighly disperse silicon dioxide is employed as an active compoundcarrier or for conversion of paste-like active compounds intopulverulent ones (E. Toricht et al., Pharmazie 32 (1977) 109).

3% Aerosil® R 972 is sufficient for the preparation of 10% ZnOsuspensions in oils, while larger amounts of hydrophilic highly dispersesilicon dioxide are required in order to achieve the same effect. Afterstorage for 100 days, according to H. v. Czetsch-Lindenwald, Pharm. Ind.27 (1965) 300, gels form, which can easily be liquefied again byshaking. The content of Aerosil® R 972 is not noticed on the skin.

Highly disperse silicon dioxide is a valuable auxiliary substance in thepreparation of suppositories: It prevents the sedimentation of suspendedactive compounds during pouring and solidification by increasing theviscosity of the molten base, influences—for example in eutecticmixtures—the melting properties and the breaking strength of theproducts, and can be used as a carrier for incorporation of liquidauxiliary substances. Here also hydrophobic highly disperse silicondioxide has advantages over the hydrophilic variant in a number of uses(H. Rupprecht et al., Deutsche Apotheker Zeitung 11 (1978) 385).

Thus, the viscosity of molten hard fat which contains 4 wt. %aminophenazone is increased considerably by 4 wt. % Aerosil® R 972,while the effect of 4 wt. % hydrophilic highly disperse silicon dioxideis low (H. Rupprecht et al., Deutsche Apotheker Zeitung 11 (1978) 385).A uniform distribution of the active compound in the suppository masscan be ensured more easily with Aerosil® R 972 in this manner than withhydrophilic highly disperse silicon dioxide. The former moreover slowsdown the release of the active compound to a greater degree than thelatter (H. Rupprecht et al. Pharmazie 32 (1977) 354). The delayedrelease of a water-soluble active compound from a Witepsol W 35suppository mass prepared with 2% Aerosil® R 972 is described in H. v.Czetsch-Lindenwald, Pharm. Ind. 27 (1965) 300. Suppositories withsustained release of active compound which comprise the water-solubleactive compound morphine sulfate, a swellable organic compound(hydroxypropylmethylcellulose) and Aerosil® R 972 are described by T.Jauw, European Patent 550 100 B1, 1996.

Medical patches, the adhesive layer of which comprises in each case 7.1wt. % of Aerosil® R 972 and hydrophilic highly disperse silicon dioxide(based on the dry matter), in addition to the active compound andvarious polymers, are described by Sekisui Chem. Ind. Com. Ltd.,Japanese Patent 0 625 6178, 1996 and Sekisui Chem. Ind. Com. Ltd.,Japanese Patent 0 625 6173, 1994 and Japan. Patent 0 431 2525, 1992).Aerosil® R 972 and hydrophilic highly disperse silicon dioxide increasethe viscosity of the solution containing polymer and active compoundwhich is applied to the support and dried. The active compounds areoptionally also adsorbed on to the surface of the highly dispersesilicon dioxide, the consequence of which is a slower and more uniformrelease of the active compound.

Aerosil® R 972 and R 812 are furthermore employed for the preparation ofpharmaceutical and cosmetic formulations bottled in pressurized gasbottles (H. v. Czetsch Lindenwald et al., J. Soc. Cosmetics Chemists 16(1965) 251).

Injection solutions based on Aerosil® R 974-containing w/o emulsions aredescribed, for example, in EP 1 179 349 A1.

Since the highest purity requirements must be met in the preparation ofpharmaceutical and cosmetic products, the considerable development ofdust in particular presents problems when working with hydrophobichighly disperse silicon dioxide types—commercially available productsare, for example, Aerosil® R 972 and Aerosil® R 974 (both Degussa),Wacker HDK H15 and Wacker HDK H20 (both Wacker) and Cab-O-Sil TS 610 andCab-O-Sil TS 620 (both Cabot). Since hydrophobic highly disperse silicondioxide types as a rule have finer particles than the hydrophilicproducts (e.g. Aerosil® 200), the dust problem is even more serioushere. Another disadvantage is the low bulk and tamped density of thehydrophobic product types, typical values are 40-50 g/l, which causes aconsiderable additional expenditure on labour and time in thepreparation of pharmaceutical and cosmetic formulations.

In the use of hydrophobic highly disperse silicon dioxide inpharmaceutical and cosmetic formulations, an improved flowability ofmixtures produced with this would furthermore be desirable, in order tobe able to achieve, for example, a higher dosing accuracy in theproduction of tablets and capsules. By this means, it would be possibleon the one hand to achieve a lower variation in tablet and capsuleweights and on the other hand to improve the profitability of processeswhich lead to these presentation forms.

The object of the present invention is to provide pharmaceutical andcosmetic formulations which avoid the disadvantages of the prior art.

The invention provides pharmaceutical and cosmetic formulations whichcomprise hydrophobic highly disperse silicon dioxide, which arecharacterized in that the silicon dioxide has a tamped density of 70 to400 g/l, determined in accordance with DIN 55943.

The invention also provides pharmaceutical and cosmetic formulationswhich comprise hydrophobic highly disperse silicon dioxide, which arecharacterized in that the silicon dioxide contains a maximum of 3.0 wt.% of water-wettable contents.

The invention also provides pharmaceutical and cosmetic formulationswhich comprise hydrophobic highly disperse silicon dioxide, which arecharacterized in that the silicon dioxide has a tamped density of 70 to400 g/l, determined in accordance with DIN 55943, and contains a maximumof 3.0 wt. % of water-wettable contents.

It has been found that when working with the formulations according tothe invention only a low development of dust occurs and the flowabilityof the formulations is significantly higher than in the case of thoseaccording to the prior art. In addition, the mechanical stability oftablets is improved and the capsule weight is increased. Furthermore,the release properties of tablets and capsules can be adjusted in acontrolled manner.

This result is surprising, since it was not possible to assume that theproperties, such as, for example, flowability or mechanical stability,of the pharmaceutical and cosmetic formulations are influenced by thetamped density of the pyrogenic silicon dioxide used. According to thearticle “Kolloidale Kieselsäure als Gelbildner [Colloidal silica as agel-forming agent]”(www.pharmazeutische-zeitung.de/pza/2001-51/pharm.5.htm) it was even tobe expected that compacted highly disperse silicas have disadvantagescompared with the non-compacted product types. Problems are describedhere with Aerosil® 200 V (tamped density 120 g/l), since it does notachieve the required thickening performance compared with the standardproducts Aerosil® 200 (tamped density 50 g/l).

It is furthermore surprising that the release of active compounds andthe disintegration time of the pharmaceutical and cosmetic formulationsis influenced by the tamped density of the hydrophobic silicon dioxideused.

It has been found that it is particularly favourable to choose a tampeddensity of the hydrophobic highly disperse silicon dioxide of between 70and 400 g/l, in particular between 75 and 300 g/l.

It is furthermore advantageous to choose hydrophobic highly dispersesilicon dioxide with a BET surface area, determined in accordance withDIN 66131, of 50 to 400 m²/g. A BET surface area of 90-300 m²/g isparticularly advantageous.

The preparation of the silicon dioxide is known, for example, fromUllmann's Encyclopedia of Industrial Chemistry, vol. A23, page 635 etseq., 5th edition, 1993.

Hydrophilic highly disperse silicon dioxide can be prepared by flamehydrolysis of chlorosilanes and is very pure chemically. It carriessilanol groups on its surface. As a result it has a high affinity forwater—it is hydrophilic—and is wetted completely by this. Alkyl groupscan be anchored chemically on the surface of the substance by reactionof the silanol groups with organic silicon compounds. The resultingproducts are then no longer wetted by water, they are hydrophobic.

Aerosil® R 972 and Aerosil® R 974 are thus formed by reacting freshlyprepared Aerosil® with dimethyldichlorosilane in an inert gas atmosphereat 400 to 600° C. in the presence of water vapour (publication seriesPigmente Nr. 5, “Hydrophobes Aerosil, Herstellung, Eigenschaften undAnwendungen” [Pigments no. 5, “Hydrophobic Aerosil, Preparation,Properties and Uses”], Degussa). Aerosil can also be partly orcompletely hydrophobized with other organosilanes. Examples of these areAerosil® R 812 (reaction with hexmethyldisilazane), Aerosil® R 805(reaction with trimethoxyoctylsilane) and Aerosil® R 202 (with siliconeoil). Processes for treatment with a surface-modifying agent are to befound, for example, in DE-A-11 63 784, DE-A-196 16 781, DE-A-197 57 210or DE-A-44 02 370.

The hydrophobic highly disperse silicon dioxide acquires its tampeddensity either directly during the preparation or in a subsequentprocess step. Thus, for example, compacting processes for pyrogenicsilicon dioxide are described in DE-A-32 38 427 and DE-A-37 41 846. Thehigh tamped density can furthermore be achieved by a grinding such as isdescribed, for example, in EP 0 637 616 A1. Granules of hydrophobichighly disperse silicon dioxide from EP 0 725 037 also have a hightamped density and are suitable according to the invention forpharmaceutical and cosmetic formulations.

Hydrophobic highly disperse silicon dioxide types which are suitableaccording to the invention and are already commercially available areAerosil® R 972 V, Aerosil® R 974 V, Aerosil® R 976 V (Degussa), Aerosil®R 8200 (Degussa), Aerosil® R 972 W (Nippon Aerosil Corporation), WackerHDK H15P, HDK H2000 and HDK H3004 (Wacker) and Reolosil DM10 (Tokuyama).Aerosil® R 972 V, Aerosil® R 974 V and Aerosil® R 972 W, and compactedAerosil® R 812 and Aerosil® 812 S are particularly suitable.

Hydrophobic highly disperse silicon dioxide is not wetted by water.Various methods are known for determination of the hydrophobicity or thedegree of hydrophobization, for example the methanol wettability ofCorning Glass.

A simple method for determination of the water-wettable contents isdescribed in the following: About 0.2 g of substance, weighed accuratelyto 0.001 g, are shaken intensively with 50 ml of water in a 250 mlpear-shaped separating funnel for 1 min. The funnel is then left tostand for one hour. During this, the predominant portion of the solidfloats up. Without shaking up the suspension again, 45 ml of the liquid,which may be slightly cloudy, are drained off dropwise and transferredto a dish which has been dried at 140° C. and cooled in a desiccator.The liquid is evaporated off completely at 110-150° C., during which itshould be ensured that no substance sprays out. After cooling in adesiccator, the dish is weighed again. The weight difference withrespect to the empty dish should be not more than 0.006 g. Thiscorresponds to 3.0 wt. % of the substance weighed out. Hydrophobichighly disperse silicon dioxide in which the water-wettable contentsmake up a max. of 3.0 wt. % are particularly suitable for thepharmaceutical and cosmetic formulations according to the invention.

Pyrogenic silicon dioxide also includes doped oxides and mixed oxides inwhich the silicon dioxide content is at least 90%. Doped pyrogenicsilicon dioxides can be obtained, for example, by the process describedin DE-A-196 50 500, in which the doping is introduced via an aerosol ofa salt solution or suspension in a flame such as is used for thepreparation of pyrogenic oxides. A mixed oxide with a silicon dioxidecontent of greater than 90 wt. % can be obtained, for example, by theprocess described in DE-A-199 19 635.

Mixtures of pyrogenic silicon dioxide with doped silicon dioxide with anSiO₂ content of 90%, with mixed oxides with an SiO₂ content of 90% ormore and/or hydrophobized silicon dioxide can also be used for theformulations according to the invention.

The hydrophobic highly disperse silicon dioxide is preferably present inthe formulation according to the invention to the extent of 0.01 to 30wt. %, particularly preferably to the extent of 0.1 to 15.0 wt. %. It isconventionally employed as an auxiliary substance, but can also be usedas an active compound, the action then primarily being a physicalaction.

Hydrophobic highly disperse silicon dioxide with a tamped density ofbetween 70 and 400 g/l can be employed according to the invention in anydesired solid, semi-solid or liquid pharmaceutical formulations(medicament forms), preferably for oral and/or topical uses, for examplein suspensions, emulsions, aerosols, injection solutions, ointments,creams, gels, pastes, suppositories, sticks, powders, dusting powders,granules, tablets, pastilles, coated tables, film-coated tablets, hardgelatine capsules, soft gelatine capsules, extrudates, microcapsules ormicrospherules. Solid medicament forms, such as, for example, powders,dusting powders, granules, tablets and capsules, are particularlypreferred.

The term pharmaceutical formulations in the context of the presentinvention also includes precursors and intermediates products for thepreparation of granules, tablets, capsules, suspensions, inspissatedjuices and inspissated drops. Such precursors and intermediate productscan have e.g. the form of a powder, granules or an extrudate.

Methods for the preparation of solid, semi-solid and liquid medicamentforms are known and are described in numerous publications and textbooksof pharmaceutical technology, cf. for example K. H. Bauer, K.-H.Frömming, C. Führer, Lehrbuch der pharmazeutischen Technologie [Textbookof Pharmaceutical Technology], 6th edition, WissenschaftlicheVerlagsgesellschaft mbH Stuttgart 1999.

The formulations according to the invention can comprise any desiredpharmaceutical active compound. Examples which may be mentioned are:α-proteinase inhibitor, abacavir, abciximab, acarbose, acetylsalicylicacid, acyclovir, adenosine, albuterol, aldesleukin, alendronate,alfuzosin, alosetron, alprazolam, alteplase, ambroxol, amifostine,amiodarone, amisulpride, amlodipine, amoxicillin, amphetamine,amphotericin, ampicillin, amprenavir, anagrelide, anastrozole, ancrod,anti-haemophilia factor, aprotinin, atenolol, atorvastatin, atropine,azelastine, azithromycin, azulene, barnidipine, beclomethasone,benazepril, benserazide, beraprost, betamethason, betaxolol,bezafibrate, bicalutamide, bisabolol, bisoprolol, botulinus toxin,brimonidine, bromazepam, bromocriptine, budesonide, bupivacaine,bupropion, buspirone, butorphanol, cabergoline, calcipotriene,calcitonin, calcitriol, camphor, candesartan, candesartan cilexetil,captopril, carbamazepine, carbidopa, carboplatin, carvedilol, cefaclor,cefadroxil, cefaxitin, cefazolin, cefdinir, cefepime, cefixime,cefmetazole, cefoperazone, cefotiam, cefoxopran, cefpodoxime, cefprozil,ceftazidime, ceftibuten, ceftriaxone, cefuroxime, celecoxib, celiprolol,cephalexin, cerivastatin, cetirizine, chloramophenicol, cilastatin,cilazapril, cimetidine, ciprofibrate, ciprofloxacin, cisapride,cisplatin, citalopram, clarithromycin, clavulanic acid, clindamycin,clomipramine, clonazepam, clonidine, clopidogrel, clotrimazole,clozapine, cromolyn, cyclophosphamide, cyclosporin, cyproterone,dalteparin, deferoxamine, desogestrel, dextroamphetamine, diazepam,diclofenac, didanosine, digitoxin, digoxin, dihydroergotamine,diltiazem, diphtheria protein, diphtheria toxoxide, divalproex,dobutamine, docetaxel, dolasetron, donepezil, dornase-α, dorzolamide,doxazosin, doxifluridine, doxorubicin, dydrogesterone, ecabet,efavirenz, enalapril, enoxaparin, eperison, epinastine, epirubicin,eptifibatide, erythropoietin-α, erythropoietin-β, etanercept,ethinyloestradiol, etodolac, etoposide, factor VIII, famciclovir,famotidine, faropenem, felodipine, fenofibrate, fenoldopam, fentanyl,fexofenadine, filgrastim, finasteride, flomoxef, fluconazole,fludarabine, flunisolide, flunitrazepam, fluoxetine, flutamide,fluticasone, fluvastatin, fluvoxamine, follitropin-α, follitropin-β,formoterol, fosinopril, furosemide, gabapentin, gadodiamide,ganciclovir, gatifloxacin, gemcitabin, gestodene, glatiramer,glibenclamide, glimepiride, glipizide, glyburide, goserelin,granisetron, griseofulvin, hepatitis B antigen, hyaluronic acid,hycosin, hydrochlorothiazide, hydrocodone, hydrocortisone,hydromorphone, hydroxychloroquine, hylan g-f 20, ibuprofen, ifosfamide,imidapril, imiglucerase, imipenem, immunoglobulin, indinavir,indomethacin, infliximab, insulin, insulin, human, insulin lispro,insulin aspart, interferon-β, interferon-α, iodine-125, iodixanol,iohexol, iomeprol, iopromide, iopromide, ioversol, ioxoprolen,ipratropium, ipriflavone, irbesartan, irinotecan, isosorbide,isotretinoin, isradipine, itraconazole, potassium chlorazepate,potassium chloride, ketorolac, ketotifen, whooping-cough vaccine,coagulation factor IX, lamivudine, lamotrigin, lansoprazole,latanoprost, leflunomide, lenograstim, letrozole, leuprolide, levodopa,levofloxacin, levonorgestrel, levothyroxine, lidocaine, linezolid,lisinopril, lopamidol, loracarbef, loratadine, lorazepam, losartan,lovastatin, lysine-acetylsalicylic acid, manidipin, mecobalamin,medroxyprogesterone, megestrol, meloxicam, menatetrenone, meningococcusvaccine, menotropin, meropenem, mesalamine, metaxalone, metformin,methylphenidate, methylprednisolone, metoprolol, midazolam, milrinone,minocycline, mirtazapine, misoprostol, mitoxantrone, moclobemide,modafinil, mometasone, montelukast, morniflumate, morphium,moxifloxacin, mycophenolate, nabumetone, nadroparin, naproxen,naratriptan, nefazodone, nelfinavir, nevirapine, niacin, nicardipine,nicergoline, nifedipine, nilutamide, nilvadipine, nimodipine,nitroglycerine, nizatidine, norethyndron, norfloxacin, octreotid,olanzapin, omeprazole, ondansetron, orlistat, oseltamivir, oestradiol,oestrogens, oxaliplatin, oxaprozin, oxolinic acid, oxybutynin,paclitaxel, palivizumab, pamidronate, pancrelipase, panipenem,pantoprazole, pantoprazole, paracetamol, paroxetine, pentoxifylline,pergolide, phenytoin, pioglitazon, piperacillin, piroxicam, pramipexole,pravastatin, prazosin, probucol, progesterone, propafenone, propofol,propoxyphen, prostaglandin, quetiapine, quinapril, rabeprazole,raloxifene, ramipril, ranitidine, repaglinide, reserpine, ribavirin,riluzole, risperidone, ritonavir, rituximab, rivastigmine, rizatriptan,rofecoxib, ropinirole, rosiglitazon, salmeterol, saquinavir,sargramostim, serrapeptase, sertraline, sevelamer, sibutramine,sildenafil, simvastatin, somatropin, somatropin, sotalol,spironolactone, stavudine, sulbactam, sulfaethidole, sulfamethoxazole,sulfasalazine, sulpiride, sumatriptan, tacrolimus, tamoxifen,tamsulosin, tazobactam, teicoplanin, temocapril, temozolomide,tenecteplase, tenoxicam, teprenone, terazosin, terbinafine, terbutaline,tetanus toxoid, tetrabenazine, tetrazapam, thymol, tiagabine, tibolone,ticarcillin, ticlopidine, timolol, tirofiban, tizanidine, tobramycin,tocopheryl nicotinate, tolterodine, topiramate, topotecan, torasemide,tramadol, trandolapril, trastuzumab, triamcinolone, triazolam,trimebutine, trimethoprim, troglitazone, tropisetron, tulobuterol,unoprostone, urofollitropin, valacyclovir, valproic acid, valsartan,vancomycin, venlafaxine, verapamil, verteporfin, vigabatrin,vinorelbine, vinpocetine, voglibose, warfarin, zafirlukast, zaleplon,zanamivir, zidovudine, zolmitriptan, zolpidem, zopiclone and derivativesthereof. However, pharmaceutical active compounds are also to beunderstood as meaning other substances, such as vitamins, provitamins,essential fatty acids, extracts of plant and animal origin and oils ofplant and animal origin.

The pharmaceutical compositions in which hydrophobic highly dispersesilicon dioxide with a tamped density of between 70 and 400 g/l can beemployed also include plant medicament formulations and homoeopathicformulations.

The pharmaceutical formulations according to the invention can also beso-called sustained release and depot medicament forms with controlledrelease of the active compounds. The pharmaceutical formulationsaccording to the invention can furthermore also be part of therapeuticsystems, such as, for example, therapeutic systems for local use andtransdermal therapeutic systems.

Further constituents of the pharmaceutical compositions can beconventional auxiliary substances, such as, for example, antioxidants,binders, emulsifiers, dyestuffs, film-forming agents, fillers, aromasubstances, flavourings, gel-forming agents, preservatives, solvents,oils, powder bases, ointment bases, acids and salts for recipeformulation, small-scale preparation and preparation of pharmaceuticalcompositions, greasing agents, disintegrating agents, suppository bases,suspension stabilizers, sweeteners, propellant gases, plasticizers andsugar substitutes.

According to an advantageous embodiment, the formulations according tothe invention can comprise as the active compound paracetamol,acetylsalicylic acid or ibuprofen.

The hydrophobic highly disperse silicon dioxide with a tamped density ofbetween 70 and 400 g/l can furthermore be used according to theinvention in cosmetic formulations of any desired consistency, forexample in powders, liquids, foams, sprays, gels, creams, ointments,pastes, sticks or tablets. The cosmetic formulations can accordingly besingle- or multi-phase systems, such as, for example, emulsions,suspensions or aerosols.

The cosmetic formulation according to the invention can be, for example,a soap; a syndet; a liquid washing or shower preparation; a bathadditive; a make-up removal composition; a peeling preparation; a skincream; a skin lotion; a face mask; a foot care composition; a sunscreencomposition; a skin tanning composition; a depigmenting composition; aninsect-repellent composition; a wet shaving composition, such as, forexample, a stick, a cream, a gel or a foam; a pre-shave preparation; anafter-shave care composition; a hair removal composition; a dentalcream; a hair shampoo; a hair care composition, such as, for example, ahair treatment course, a rinse or a conditioner; a permanent wavecomposition; a straightening composition, a style setting composition,such as, for example, a hair setting composition, a hair spray, a hairlacquer, a hair gel or a hair wax; a hair colour-modifying composition,such as, for example, a blonding composition, a hair-colouringcomposition, a toner or a colour enhancer; a deodorant or anantiperspirant composition, such as, for example, a stick, a roll-on, alotion, a powder or a spray; a face make-up, such as, for example, atinted day cream, a powder cream, a face powder, a cream make-up or arouge; an eye make-up, such as, for example, a lid shadow, a mascara, akajal stick, an eyeliner or an eyebrow pencil; a lip care composition; adecorative lip care composition, such as, for example, a lipstick, a lipgloss or a lip contour pencil; or a nail care composition, such as, forexample, a nail varnish, a nail varnish remover, a cuticle remover, anail hardener or a nail care cream.

The present invention also provides a cosmetic formulation whichcomprises the hydrophobic highly disperse silicon dioxide and at leastone constituent chosen from absorbents, astringents, antimicrobialsubstances, antioxidants, antiperspirants, antifoams, antidandruffactive compounds, antistatics, binders biological additives, bleachingagents, chelating agents, deodorizing agents, emollients, emulsifiers,emulsion stabilizers, depilatory agents, dyestuffs, humectants,film-forming agents, aroma substances, flavourings, hair-colouringagents, preservatives, corrosion protection agents, cosmetic oils,solvents, oral care substances, oxidizing agents, plant constituents,buffer substances, reducing agents, abrasives, surfactants, propellantgases, opacifying agents, UV filters and absorbers, denaturants,viscosity regulators and vitamins.

EXAMPLES

Pharmaceutical Formulations:

The pulverulent starting substances are weighed accurately to 0.01 g inthe stated sequence and mixed manually in a 5 glass bottle. This mixtureis sieved through a sieve of mesh width 0.71 mm and homogenized in aglass bottle with a Turbula mixer for five minutes. TABLE 1 Formulations(data in wt. %) Formulation 1 Formulation 2 Formulation 3 Paracetamol83.3  — — Acetylsalicylic — 83.3  — acid Lactose — 79.7  Powderedcellulose 13.3  10.4  20.0  Maize starch 3.0 5.0 — Magnesium stearate0.1 — — Stearic acid — 1.0 — Silicon dioxide 0.3 0.3 0.3

Aerosil® R 972 (tamped density approx. 50 g/l; comparison examples) andAerosil® R 972 V (tamped density 90 g/l; according to the invention) areused as the silicon dioxide.

The flow rating and/or poured cone height are determined as a measure ofthe flowability. Furthermore, tablets are pressed and capsules filledwith the formulations according to table 1.

Hard Gelatine Capsules

Using a capsule filling apparatus, hard gelatine capsules of size 1 withan empty weight of 71-78 mg are filled with the formulations accordingto table 1. In each case 60 capsules are prepared and the averagecapsule weight is determined.

The values for formulation 1 are to be found in tab. 2, those forformulation 2 in tab. 3 and those for formulation 3 in tab. 4.

Tablets

The formulations according to table 1 are pressed at the same pressingpressure using an eccentric press (EKO, Korsch) to give tablets with aweight of approx. 600 mg. The tablet hardness is determined on in eachcase 10 tablets by means of a semi-automatic hardness tester. Thedisintegration time in water warmed to 37° C. (manufacturer Erweka,model ZT 31) is moreover determined on six tablets.

The values for formulation 1 are to be found in tab. 2, those forformulation 2 in tab. 3 and those for formulation 3 in table 4. TABLE 2Properties of formulation 1 Tamped density Poured cone TabletDisintegration Capsule SiO₂ [g/l] height (cm) hardness [N] time [s]weight [mg] 50 2.4 59 25 380 90 2.2 79 30 399*Poured cone height determined in accordance with: Publication seriesPigmente [Pigments], number 31 from Degussa, 6th edition. The lower thepoured cone height of a powder mixture, the better the flow properties.

TABLE 3 Properties of formulation 2 Tamped density Poured cone TabletDisintegration Capsule SiO₂ [g/l] height [cm] hardness [N] time [s]weight [mg] 50 2.4 93 25 375 90 2.2 95 35 381

TABLE 4 Properties of formulation 3 Tamped density Poured cone TabletDisintegration Capsule SiO₂ [g/l] height [cm] hardness [N] time [s]weight [mg] 50 2.3 141 25 345 90 2.2 238 75 350

The formulations according to the invention show clear advantages inflow properties, tablet hardness and capsule weight. They moreover havea longer disintegration time.

Pharmaceutical Auxiliary Substance Mixtures:

198.0 g Avicel PH101 and in each case 2.0 g Aerosil® R 972 (Degussa;tamped density 50 g/l; comparison example), Aerosil® R 972 V (Degussa;tamped density 90 g/l; according to the invention) and Aerosil® R 972 W(Nippon Aerosil Corporation; tamped density 160 g/l) are premixedmanually in a 1 l wide-necked bottle and the mixture is sieved through a0.71 mm sieve and mixed in a free-fall mixer (Turbula) for 10 min at 42revolutions per minute. The flow rating and poured cone height of themixture were then determined.

The results of the experiments are summarized in table 5. TABLE 5Properties of the pharmaceutical auxiliary substance mixtures Tampeddensity Poured cone height SiO₂ [g/l] Flow rating [cm] 50 3 2.0 90 2.51.9 160 2 1.75*Flow rating and poured cone height determined in accordance with:Publication series Pigmente [Pigments], number 31 from Degussa, 6thedition. The lower the flow rating or poured cone height of a powdermixture, the better the flow properties.

Determination of the Water-wettable Contents of Hydrophobic HighlyDisperse Silicon Dioxide:

About 0.2 g of substance, weighed accurately to 0.001 g, are shakenintensively with 50 ml of water R in a 250 ml pear-shaped separatingfunnel for 1 min. The funnel is then left to stand for one hour. Duringthis, the predominant portion of the solid floats up. Without shaking upthe suspension again, 45 ml of the liquid, which may be slightly cloudy,are drained off dropwise and transferred to a dish which has been driedat 140° C. and cooled in a desiccator.

The liquid is evaporated off completely at 110-150° C., during which itshould be ensured that no substance sprays out. After cooling in adesiccator, the dish is weighed again. The weight difference withrespect to the empty dish should be not more than 0.006 g. Thiscorresponds to 3.0 wt. % of the substance weighed out. TABLE 6Water-wettable contents of the hydrophobic highly disperse silicas usedAerosil ® Aerosil ® Product 972 972 V CP 1 CP 2 Tamped density (g/l) 5090 50 90 Water-wettable 3.0 2.0 7.0 6.0 contents (%)

The comparison products CP 1 and CP 2 are prepared analogously toAerosil® R 972 and Aerosil® R 972 V, but with a starting amount ofdimethyldichlorosilane reduced by 10%. The products therefore have asomewhat higher content of water-wettable contents. Pharmaceuticalformulations 2 and 3 from table 1 are also prepared with CP 1 and CP 2.The analytical data of the formulations are summarized in tables 7 and8. TABLE 7 Properties of formulation 2 Tablet Capsule Poured conehardness Disintegration weight Product height [cm] [N] time [s] [mg]Aerosil ® R 972 2.4 93 25 375 CP 1 2.6 80 15 355 Aerosil ® R 972 V 2.295 35 381 CP 2 2.4 88 20 368

TABLE 8 Properties of formulation 3 Tablet Capsule Poured cone hardnessDisintegration weight Product height [cm] [N] time [s] [mg] Aerosil ® R972 2.3 141 25 345 CP 1 2.5 125 20 335 Aerosil ® R 972 V 2.2 238 75 350CP 2 2.4 202 60 340

The experiments show that in addition to the tamped density, thewater-wettable contents have a considerable influence on the propertiesof the pharmaceutical formulations. Hydrophobic highly disperse silicondioxide in which the water-wettable contents make up a max. of 3.0 wt. %are accordingly particularly suitable for the pharmaceutical andcosmetic formulations according to the invention.

1. Pharmaceutical and cosmetic formulations comprising an activeingredient and an auxiliary amount of hydrophobic highly dispersesilicon dioxide, having a tamped density of 70 to 400 g/l.
 2. Theformulations according to claim 1, wherein the hydrophobic highlydisperse silicon dioxide has a BET surface area between 50 and 400 m²/g.3. The formulations according to claim 1, wherein the amount ofhydrophobic highly disperse silicon dioxide is from 0.01 to 30 wt. %. 4.The formulations according to claim 1, wherein the silicon dioxidecontains a maximum of 3.0 wt. % of water-wettable contents.
 5. Theformulations according to claim 1, wherein the silicon dioxide has atamped density of 70 to 400 g/l, determined in accordance with DIN55943, and contains a maximum of 3.0 wt. % of water-wettable contents.